Huntington's Disease Biomarkers Appear 24 Years Before Clinical Symptoms

Heidi Splete

June 08, 2020

Early signs of neurodegeneration appeared in young adult carriers of the Huntington's disease gene mutation approximately 24 years before the clinical onset of symptoms, according to a study published in the June Lancet Neurology. The data come from the Huntington's disease Young Adult Study (HD-YAS) conducted in the United Kingdom.

The genetic cause of Huntington's disease provides a potential target for biomarker treatment, wrote joint first authors Rachael I. Scahill, PhD, and Paul Zeun, BMBS, of University College London and colleagues.

"A detailed characterization of the premanifest period in Huntington's disease is crucial for disease staging, informing the optimum time to initiate treatments, and identifying biomarkers for future trials in people with premanifest Huntington's disease (preHD)," they said.

Identifying Biomarkers of Pre-Huntington's Disease

For their study, the researchers recruited 64 young adults with presymptomatic Huntington's disease (preHD) and 67 controls, with an average age of 29 years. Brain imaging was conducted between Aug. 2, 2017, and April 25, 2019. Individuals with preexisting measurable cognitive and psychiatric disorders were excluded.

The researchers found no significant evidence of cognitive or psychiatric impairment in the preHD group at 23.6 years from the predicted onset of symptoms. The preHD group showed smaller putamen volumes, compared with controls, but this difference had no apparent relation to the timing of symptom onset, the researchers said.

Brain imaging revealed elevations in the CSF mutant huntingtin, neurofilament light protein (NfL), YKL-40, and plasma NfL among individuals with preHD, compared with controls. Of these, CSF NfL showed the highest effect size of measures in the study and showed a significant increasing association with estimated years to the onset of clinical symptoms of HD carriers. Overall, 53% of individuals with preHD had CSF NfL values in the normal range, and 47% had elevated values, compared with controls.

"NfL is therefore a potential candidate to provide a measure of disease progression in early preHD and might eventually be used as a marker of response to treatment in future preventive trials," the researchers said.

The study findings were limited by several factors including potential underpowering to detect associations with age and CAG gene segment repeats, the researchers noted.

However, "By identifying a cohort of individuals with preHD and no detectable functional impairment but who begin to exhibit subtle elevations in select biological measures of neurodegeneration, we have highlighted a crucial point early in the disease process," they concluded.

"Intervening at this stage might offer the prospect of delaying or preventing further neurodegeneration while function is intact, giving gene carriers many more years of life without impairment," they added.

What Is the Best Window for Treatment?

The study is "particularly important since the absence of any subclinical symptoms in preHD individuals far from onset shows that the abnormal developmental aspect of Huntington's disease has no substantial effect on adults' clinical pattern," wrote Anne-Catherine Bachoud-Lévi, MD, of Université Paris Est, Créteil, France, in an accompanying comment.

"The most robust findings of [the study] are the sensitiveness of NfL, compared with mutant huntingtin in CSF of individuals with preHD, and that degenerative rather than developmental disorders are clinically relevant," she said. However, potential limitations to the study include the exclusion absence of language and calculation as part of the cognitive assessments, she noted. "Ideally, more sensitive cognitive tasks including these domains should be designed for preHD participants."

In addition, the risks versus benefits of any long-term treatment must be considered, Dr. Bachoud-Lévi noted.

"The best window for treatment should instead target the time when a detectable subclinical slope of cognitive performance allows for predicting disease onset within a few years," she said. "Turning to machine learning methodology, such as that in oncology, might also permit combining the best window and the best disease-modifying therapy for individuals with preHD," she added.

The study was supported by the Wellcome Trust, CHDI Foundation. The researchers had no financial conflicts to disclose. Dr. Bachoud-Lévi disclosed grants and personal fees from Roche, and grants from the French Ministry of Health and Direction de la Recherche Clinique.

SOURCES: Scahill RI et al. Lancet Neurol. 2020 June;19:502-12; Bachoud-Lévi A-C. Lancet Neurol. 2020 June;19:473-5.

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